title: Structure-activity relationships of 1,3-benzoxazole-4-carbonitriles as novel antifungal agents with potent in vivo efficacy.
abstract: A series of 1,3-benzoxazole-4-carbonitriles was synthesized and evaluated for its antifungal activity, solubility, and metabolic stability. Among those compounds, 4-cyano-N,N,5-trimethyl-7-[(3S)-3-methyl-3-(methylamino)pyrrolidin-1-yl]-6-phenyl-1,3-benzoxazole-2-carboxamide (16b) exhibited potent in vitro activity against Candida species, higher water solubility, and improved metabolic stability compared to lead compound 1. Compound 16b showed potent in vivo efficacy against mice Candida infection models and good bioavailability in rats.
authors.affiliation: Lead Discovery & Optimization Research Laboratories II, Daiichi Sankyo Co., Ltd., Tokyo, Japan. kuroyanagi.junichi.d5@daiichisankyo.co.jp
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kuroyanagi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kanai
authors.forename: Takao
authors.initials: T
authors.lastname: Horiuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeshita
authors.forename: Shozo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Issei
authors.initials: I
authors.lastname: Achiwa
authors.forename: Kumi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D002175:Candida / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy; D051379:Mice; D008826:Microbial Sensitivity Tests; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: C558713:4-cyano-N,N,5-trimethyl-7-((3S)-3-methyl-3-(methylamino) pyrrolidin-1-yl)-6-phenyl-1,3-benzoxazole-2-carboxamide; D000935:Antifungal Agents; D001583:Benzoxazoles; D009570:Nitriles